The study is to determine the safety, tolerability, maximum tolerated dose (MTD) and feasibility of allogeneic γδ T cell therapy combining with/without chemotherapy in subjects with advanced solid cancers. The study is an adaptive design that has 2 stages: Stage 1 - dose escalation, Stage 2 – efficacy.
Full Title of Study: “A PhaseⅠ/Ⅱ Study of Ex Vivo Expanded Allogeneic γδ T Cell Therapy for Treatment of Patients With Advanced Solid Cancers Which Have No Objective Response to Current Treatment”
- Study Type: Interventional
- Study Design
- Allocation: N/A
- Intervention Model: Single Group Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: December 31, 2023
This is an open-label, single-center, phase I/Ⅱstudy to evaluate the safety and feasibility of allogeneic γδ T cell therapy and three target dose levels between 2×10^6 – 5×10^7/kg per infusion will be tested. 4-6 doses will be given at an interval of 3-4 weeks into subjects with advanced solid cancers.Whether chemotherapy should be combined or not depends on the specific condition of the patient. The study is an adaptive design that has 2 stages: Stage 1 – dose escalation, Stage 2 - efficacy.A typical 3+3 design will be used to determine the safe regimen based on the incidence of dose-limiting toxicity (DLT) in Stage 1. The identified safe regimen will be used to further confirm safety and efficacy in Stage 2.
- Biological: Allogeneic γδ T cells
- During Stage 1, Subjects will receive 4-6 cycles of allogeneic γδ T cells with three target dose levels , 2×10^6/kg , 1×10^7/kg ,5×10^7/kg per infusion to determine the safe regimen. The identified safe regimen will be used to further confirm safety and efficacy in Stage 2. Whether chemotherapy should be combined or not depends on the specific condition of the patient.
Arms, Groups and Cohorts
- Experimental: Allogeneic γδ T cell Group
- Subjects will receive allogeneic γδ T cells with/without chemotherapy.
Clinical Trial Outcome Measures
- Incidence of dose-limiting toxicity (DLT)
- Time Frame: Baseline to Day 30
- The dose escalation strategy will follow the Food and Drug Administration Guideline for design of early phase clinical trials of cellular therapy products.
- Incidence of severe adverse events
- Time Frame: Baseline to Day 100
- Safety of the γδ T cell infusion will be based on the risk of treatment-related severe adverse events as identified in the National Cancer Common Terminology Criteria for Adverse Events (CTCAE) version 5.
- Objective Response Rate
- Time Frame: Baseline to 2years
- Objective clinical response will be assessed by investigators every 2 circles during the treatments and every 2 months after treatment until 2 years after the start of 1st cycle of treatment.
- Duration of Response
- Time Frame: Baseline to 2years
- The duration of objective response in patients will be recorded until 2years after the start of 1st cycle of treatment
- Overall Survival
- Time Frame: Baseline to 2years
- Observation for overall survival l (OS) will be recorded until 2years after the start of 1st cycle of treatment.
- Progress Free Survival
- Time Frame: Baseline to 2years
- Observation for progression-free survival (PFS) will be recorded until 2years after the start of 1st cycle of treatment
- Intervention Treatment-related adverse events(AEs)
- Time Frame: Baseline to 12 months
- Incidence, nature ,and severity of adverse events will be graded according to the NCI CTCAEv5.0.
Participating in This Clinical Trial
1. Patients with histological confirmation of advanced solid tumor and failed to reach CR or PR with at least 2 circles of current standard treatments ; Patients histologically confirmed of solid tumors for which standard treatments are unavailable ,with/without any prior treatments(eg. pancreatic cancer, cholangiocarcinoma ect.). 2. Patients should sign informed consent form voluntarily before the trail and comply with the requirements of this study. 3. Age 18 years up to the age of 65 (≤65), gender unlimited. 4. Patients with at least one evaluable imaging lesion ≥10 mm in diameter (≥15 mm for nodal lesions). 5. Eastern Cooperative Oncology Group (ECOG) Performance score≤2. 6. Patient with adequate bone marrow reserve (Haemoglobin ≥10g/dl, Absolute Neutrophil Count (ANC)≥1,500/mm3, Platelet≥100,000/mm3), hepatic function (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5x upper limit of normal or ≤ 5 x ULN with liver metastases，Total bilirubin ≤ 1.5 x ULN), renal function (Creatinine ≤ 1.5 x upper limit of normal (ULN)) and cardiac function (Left ventricular ejection fraction of ≥50% by ECHO). 7. Patient with life expectancy of at least 3 months. 8. Patient without bleeding and coagulation disorders. 9. Patient without obvious genetic diseases. 10. Patient's last treatment was completed ≥4 weeks prior to enrollment and had recovered to ≤ grade 1 toxicity. 11. Male and female patients of reproductive potential must agree to use birth control during the study and for at least 12 weeks post study. Exclusion Criteria:
1. Patients who received or are to receive any other cell therapy within 4 weeks before the planned day for the first allogeneic γδ T cell administration. 2. Patients who participated or are to participate in other interventional clinical trial within 30 days before the planned day for the first allogeneic γδ T cell administration. 3. Uncontrolled serious active infection (such as sepsis, bacteremia and fungemia，HBV, HCV, HIV, TP, CMV or EBV infection). 4. Systemic steroid therapy or other immune-suppressants (except in cases where the patient is receiving treatment with replacement doses for adrenal insufficiency). 5. Patient's cardiac function meets any of the following conditions: Left ventricular ejection fraction (LVEF)≤45%； Class III or IV heart failure according to the NYHA Heart Failure Classifications； QTcB>450 msec； Other cardiac disease that investigators judge is not suitable for enrollment. 6. Pregnancy or lactation before or during the trial. A urine pregnancy test will be carried out at screening. 7. Less than 4 weeks since systemic anti-cancer therapy (tyrosine kinase inhibitors, immunotherapy, hormonal therapy, radiotherapy). 8. If immune checkpoint inhibitors (ICI) were given, a 3- month interval was required between the last dose of ICI and the first injection of γδ T cells. 9. Patients with history of prior organ or bone marrow transplantation. 10. Patients with systemic vasculitis, or with active or uncontrolled autoimmune diseases, as well as primary or secondary immunodeficiency diseases. 11. History of epilepsy or other active central nervous system disorders. 12. Patients inoculated live vaccine within 6 weeks before screening. 13. Allergic constitution, history of allergies to blood products, known to be allergic to any substances in the protocol（such as Zoledronate or similar）. 14. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other medical condition that precludes surgery. Also, psychiatric illness/social situations that would limit compliance with study requirements.二 15. Any other situations that investigators believe the risk of the subjects is increased or results of the trial are disturbed Donor Inclusion Criteria:
1. Sign informed consent form. 2. Age 18 years up to the age of 50 (≤50), gender unlimited. 3. Relative to patients (unrestricted to blood relationship). 4. Apheresis available. 5. PLT≥100×109/L with normal APTT or PT. 6. preculture ofγδ T cells meets the requirements of massive amplification and detection. Donor Exclusion Criteria:
1. History of any severe clinical diseases or other severe organic diseases, including any history of clinically significant systematic diseases such as cardiovascular, urinary, circulatory, respiratory, neurological, psychiatric, digestive and endocrine diseases. History of high blood pressure or systolic pressure>140 mmHg, diastolic pressure>90 mmHg in screening stage. Any situation that investigators believe is clinically significant or with other severe diseases unsuitable of apheresis. 2. Arterial thrombosis or venous thrombosis history 12 months prior to the trial or hemorrhagic tendency or history 2 months prior to the trial; oral administration of anticoagulation drugs (e. g. aspirin and warfarin). 3. Active or history of autoimmune diseases including but not restricted to SLE, psoriasis, RA, IBD and HT. Apart from hypothyrosis which can be controlled by hormone replacement therapy, skin diseases without systemic therapy and celiac disease which is fully controlled. 4. HIV-Ab, TP-Ab, HCV-Ab, HBsAg, HBeAg, HBeAb or HBcAb positive. 5. Any symptom, sign or laboratory examination abnormality suggesting acute or subacute infection (e.g. fever, cough, urinary irritation, skin infectious wound). 6. Female who are pregnant or cannot stop lactating. 7. Those who cannot communicate with medical staff due to mental illness or language disabilities. 8. Other unsuitable conditions that investigators believe unsuitable for the donation.
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: 70 Years
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Chinese PLA General Hospital
- Provider of Information About this Clinical Study
- Principal Investigator: Han weidong, Professor – Chinese PLA General Hospital
- Overall Official(s)
- Weidong Han, M.D, Principal Investigator, Biotherapeutic Department of Chinese PLA General Hospital
- Yanshan Li, Principal Investigator, Biotherapeutic Department of Chinese PLA General Hospital
- Kaichao Feng, Principal Investigator, Biotherapeutic Department of Chinese PLA General Hospital
- Overall Contact(s)
- Weidong Han, M.D, +8601066937463, firstname.lastname@example.org
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